Until recently, the only information on the growth rate of prostate tumors has been derived from cross-sectional histological labeling studies, autopsy data and clinical studies of patients managed expectantly. However, serial measurements of prostate specific antigen (PSA) may now allow studies of the natural history of the earliest stages of prostate cancer. Frozen sera samples from the Baltimore Longitudinal Study of Aging have been used to compare the patterns of change in PSA levels in men with and without prostate cancer up to 25 years before the diagnosis of cancer. Men with no prostatic disease exhibited a slow linear increase in PSA levels, whereas benign prostatic hyperplasia cases showed a gradual acceleration in the rate of change in PSA. In contrast, cancer cases exhibited an early linear phase followed by an exponential phase of increase in PSA levels before diagnosis. On average, the exponential phase of PSA increases began 7 to 9 years before the tumors were detected clinically. Thus, there is a significant window of opportunity for early detection of prostate cancer. The changes in PSA observed in men with and without prostate cancer are consistent with available information on prostatic growth and the long natural history of prostate cancer. A better understanding of the various factors that affect serum PSA levels may allow more effective use of PSA measurements to detect early stage tumors and predict the biological potential of a tumor.